The Polypill for Secondary Prevention

Is Entering the Cardiovascular Field:

Worldwide Interest Based on Better

Adherence and Economics

Jose M. Castellano, MD, PhD

Clinical Trials Coordinator, CNIC, Madrid, Spain

Adjunct Associate Professor, Mount Sinai School of

Medicine

Nothing to disclose

A Polypill Strategy for Secondary Cardiovascular Prevention

1. A new Global CVD Scenario: focus on accessibility to CV drugs

2. A polypill strategy to improve adherence to CV Medication

3. A Cost effective strategy for CV Prevention

4. From Concept to Reality

A Polypill Strategy for Secondary Cardiovascular Prevention

1. A new Global CVD Scenario: focus on accessibility to CV drugs

2. A polypill strategy to improve adherence to CV Medication

3. A Cost effective strategy for CV Prevention

4. From Concept to Reality

Castellano JM et al. J Am Coll Cardiol. 2014 Aug 12;64(6):613-621

CARDIOVASCULAR DISEASE IN 2011

Global Cardiovascular Disease

Fuster, V. Nat. Rev. Cardiol. advance online publication 30 September 2014; doi:10.1038/nrcardio.2014.137

8 out of 10 cardiovascular deaths occur in LMIC

0 10 20 30 40 50

High Income

Upper Middle Income

Low Middle Income

Low Income

0 10 20 30 40 50

High Income

Upper Middle Income

Low Middle Income

Low Income

Male Female

Previous MI Previous Stroke

Yusuf et al. Lancet, 2011, 378: 1231

Global treatment rates with antiplatelet, statin and BP lowering

A Polypill Strategy for Secondary Cardiovascular Prevention

1. A new Global CVD Scenario: focus on accessibility to CV drugs

2. A polypill strategy to improve adherence to CV Medication

3. A Cost effective strategy for CV Prevention

4. From Concept to Reality

A Polypill Strategy for Secondary Cardiovascular Prevention: from concept to reality

Reduces the number of components to simplify treatment regimen:

Improves adherence

Cost Effective Strategy Improves affordability

Favors global accessibility to pharmacologic treatment

Medication Non-Adherence …America’s other drug problem

Medication Non-Adherence

ADHERENCE TO LONG TERM THERAPIES: EVIDENCE FOR ACTION. WHO 2003

Social/

Economic

Health Care

System

Condition-

Related Therapy-

related

Patient-

related

Age and race Family size Marital status

Patient Provider relationship

Comorbidities (depression)

Polypharmacy Side effects

Cognitive impairment

Socio economic status Education Employment Income

Overworked HCP Communication

Asymptomatic condition

Complexity of treatment Lack of immediate benefit of therapy

Assumption once person feels better: discontinuation

Health Illiteracy Lack of incentives

Long duration, chronic disease

Social stigma Media influence

Cost of medication Lack of empathy Frequent changes of treatment

Duration Fear of side effects

The Five Dimensions of Non Adherence

Medication Non-Adherence

ADHERENCE TO LONG TERM THERAPIES: EVIDENCE FOR ACTION. WHO 2003

Social/

Economic

Health Care

System

Condition-

Related Therapy-

related

Patient-

related

Age and race Family size Marital status

Patient Provider relationship

Comorbidities (depression)

Polypharmacy Side effects

Cognitive impairment

Socio economic status Education Employment Income

Overworked HCP Communication

Asymptomatic condition

Complexity of treatment Lack of immediate benefit of therapy

Assumption once person feels better: discontinuation

Health Illiteracy Lack of incentives

Long duration, chronic disease

Social stigma Media influence

Cost of medication Lack of empathy Frequent changes of treatment

Duration Fear of side effects

The Five Dimensions of Non Adherence

Chowdhury R et al. EHJ, 2013;34(38):2940-8.

n=1,978,919 (135,627 CVD events and 94,126 cases of all-cause mortality)

Prevalence of Good Adherence to CV Medications

Adherence to any CVD Medication Adherence to STATINS Adherence to ANTIHYPERTENSIVES Adherence to ASPIRIN Adherence to ANTIDIABETIC AGENTS

34

12

11

2

2

1.230.382

771.323

363.819

11.068

1112

0,60 (0,52-0,68)

0,54 (0,41-0,67)

0,54 (0,42-0,77)

0,70 (0,49-0,91)

0,69 (0,59-0,78)

0 0.2 0.4 0.6 0.8 1

Prevalence of Good Adherence (%)

No. of Studies

No. of Participants Proportion (95% CI)

Chowdhury R et al. EHJ, 2013;34(38):2940-8.

n=1978919 (135 627 CVD events and 94 126 cases of all-cause mortality)

Relative Risks for ANY CVD in good vs. poor adherence to major CV medication

Adherence to any CVD Medication Adherence to STATINS Adherence to ANTIHYPERTENSIVES Adherence to ACEI/ARB Adherence to ASPIRIN

33

17

13

4

3

1.615.126

1,055,920

552,143

68,780

15,253

0,80 (0,77-0,84)

0,85(0,81-0,89)

0,81 (0,76-0,86)

0,75 (0,55-1,01)

0,60 (0,31-1,16)

No. of Studies

No. of Participants

RR(95% CI) No. of

CVD Events

135.627

96,216

36,186

4643

2274

Chowdhury R et al. EHJ, 2013;34(38):2940-8.

n=1978919 (135 627 CVD events and 94 126 cases of all-cause mortality)

Relative Risks for ALL-CAUSE-MORTALITY good vs. Poor adherence to major CV medication

Adherence to any CVD Medication Adherence to STATINS Adherence to ANTIHYPERTENSIVES Adherence to ACEI/ARB Adherence to ASPIRIN

23

11

11

4

3

533,381

291,864

205,598

62,196

12,980

0,65 (0,57-0,67)

0,55(0,81-0,89)

0,71 (0,64-0,78)

0,74 (0,69-0,80)

0,45 (0,16-1,29)

No. of Studies

No. of Participants

RR(95% CI)

9% of CV deaths EU attributable to poor adherence Good adherence to CV therapies could be associated with a 20% lower risk

of CVD and 35% reduced risk of all cause mortality

No. of DEATHS

94,126

29,605

12,228

886

1573

Database non-concurrent cohort study

Presented ESC 2014 Registry Hotline Aug 31, 2014

Adults following MI & ACEI and statin fill in 6 months

7,107

Fully adherent

PDC > 80% 1,761 (43%)

Partially adherent

PDC 40-79% 1,263 (31%)

Non-adherent

PDC < 40% 1,031 (26%)

Adults following MI & ACEI and statin fill in 6 months

With a 6 month pre-period 4,015

7,012 No fill of both ACEI and Statin during the 6 months after the MI

1,331 excluded (diagnostic codes) • 29% mental disease • 1%maternity or delivery • 10% hospice or respite care • 23% nursing facility • 33% ARB fill during 6 months post-

MI • 4% MI as a subsequent episode

Adults following MI & ACEI and statin fill in 6 months

5,776

1,761 without a 6 month pre-period

Adults following MI Between 1/1/2010 - 2/28/2013

14,119

Time to Major cardiac Event by Adherence Levels

Strategies to Improve Adherence

Strategies to Improve Adherence

Strategies to Improve Adherence

What Is Effective in Helping Chronic Non-Adherence: Sobering Findings

Annals of Internal Medicine Systematic Review 2012 and the Cochrane Review:

• 36 of 83 interventions in 70 RCTs improved adherence, but only 25 led to clinical improvement

• Almost all were complex interventions but led to only modest improvements—case management and patient education with behavioral support

• Cost effectiveness needs to be studied

• Policy interventions aimed at co-payment costs or drug coverage were also effective

Vishwanathan M et al. Annals of Internal Medicine 2012; 157:785-795

Strategies to Improve Adherence

S — Simplify the regimen

I — Impart knowledge

M— Modify patient beliefs and behavior

P — Provide communication and trust

L — Leave the bias

E — Evaluate adherence

http://www.acpm.org/?MedAdherTT_ClinRef

Primary Outcomes – Adherence at 12 months

Kanyini-GAP IMPACT UMPIRE Overall

96/249 (38.6%) 106/218 (48.6%) 602/925 (65.1%)

196/249 (78.7%) 172/233 (73.8%) 827/935 (88.4%)

1 1/4 4

2.04 (1.72,2.42) <0.01 1.52 (1.30,1.78) <0.01 1.36 (1.29, 1.43) <0.01 1.58 (1.32, 1.90) <0.01

Usual Care Polypill

Favors Usual Care

Favors Polypill

Risk Ratio (95% CI) P value

SPACE Program Results

UMPIRE: n= 2002, India & W. Europe Kanyini-GAP: n=623 in Australia, half indigenous

IMPACT: n=513 in NZ, half indigenous

64 Clinical Sites in Spain, Italy, Argentina, Brazil and Paraguay

Fixed-dOse Combination DrUg for

Secondary Cardiovascular Prevention

Castellano JM et al. A polypill strategy to improve adherence: results from FOCUS Project. J Am Coll Cardiol. 2014

Sept 1

PROJECT OVERVIEW Phase 1: Observational

To determine the proportion of post-MI

patients receiving appropriate secondary

prevention

To estimate the level of patient

adherence

To identify factors that contribute to poor

adherence.

Morisky Green: Assessment of

adherence

Phase 2: Prospective RCT

To compare adherence to treatment in

post MI patients receiving a FDC vs.

those with conventional treatment (3

drugs provided separately)

Primary Endpoint: Adherence measured

by Morisky-Green and Pill Count

combined

To evaluate the effect of TRINOMIA on

BP and LDL-C

Safety and tolerability of TRINOMIA

3 drugs

separately

FUSTER-CNIC-FERRER

TRINOMIA Aspirin 100

Ramipril 2,5-5-10 Simvastatin 40

2118

Adherence: MG + Pill

Count

695

Phase 1

Phase 2

R

9 months

Castellano JM et al. J Am Coll Cardiol. 2014; 64

FOCUS Phase 1 – Results

MORISKY GREEN: EVALUATION OF ADHERENCE

(N=2118)

45.5

49.8

50.3

49.3

36.4

40

30.1

17.7

0 10 20 30 40 50 60

Global

Europe

Italy

Spain

America

Argentina

Brazil

Paraguay

% adherent (Original Morisky-Green = 20)

Castellano JM et al. J Am Coll Cardiol. 2014 Sept 1

FOCUS Phase 1 Results FACTORS THAT INFLUENCE ADHERENCE

Clinical: AMI date, more pills*, complex treatments*

Socio demographics: Younger age, Illiteracy*, Distance

from medical centerƚ

Risk factors: BMI*, Smoking*, Sedentary lifestyle*

Psychosocial: Depression, Social Supportƚ, lack of

Insuranceƚ

*Individual level intervention ƚSystems intervention

Castellano JM et al. J Am Coll Cardiol. 2014 Sept 1

FOCUS Phase 1 Results

DETERMINANTS OF LACK OF ADHERENCE

1

NON-ADHERENT ADHERENT

Younger age <50

Depression severity

Complexity of tx

% Insurance cover

Degree social support

0

Results from country-adjusted stepwise variable selection model

1.5

Castellano JM et al. J Am Coll Cardiol. 2014 Sept 1

PROJECT OVERVIEW Phase 1: Observational

To determine the proportion of post-MI

patients receiving appropriate secondary

prevention

To estimate the level of patient

adherence

To identify factors that contribute to poor

adherence.

Morisky Green: Assessment of

adherence

Phase 2: Prospective RCT

To compare adherence to treatment in

post MI patients receiving a FDC vs.

those with conventional treatment (3

drugs provided separately)

Primary Endpoint: Adherence measured

by Morisky-Green and Pill Count

combined

To evaluate the effect of TRINOMIA on

BP and LDL-C

Safety and tolerability of TRINOMIA

3 drugs

separately

FUSTER-CNIC-FERRER

TRINOMIA Aspirin 100

Ramipril 2,5-5-10 Simvastatin 40

2118

Adherence: MG + Pill

Count

695

Phase 1

Phase 2

R

9 months

Castellano JM et al. J Am Coll Cardiol. 2014 Sept 1

FOCUS Phase 2 Results

POLYPILL VS. CONTROL AT 9 MONTHS: EFFECT ON

ADHERENCE

p=0.049

MORISKY GREEN (20)

pe

rce

nta

ge

Pe

rce

nta

ge

p=0.012

p=0.364

Castellano JM et al. J Am Coll Cardiol. 2014 Sept 1

A Polypill Strategy for Secondary Cardiovascular Prevention

1. A new Global CVD Scenario: focus on accessibility to CV drugs

2. A polypill strategy to improve adherence to CV Medication

3. A Cost effective strategy for CV Prevention

4. From Concept to Reality

Castellano JM et al. J Am Coll Cardiol. 2014 Aug 12;64(6):613-621

CARDIOVASCULAR DISEASE IN 2011

Heidendreich P. et al, Circulation 2011; 123:933-944

Projections of Prevalence

%∆ 9.9

%∆ 200

Projections of Direct Cost (Billions USD)

Impact on Health Care Costs

Iuga A. et al. Risk Management and Health Care Policy. 2014:7 35-44

Medication Non-Adherence

Poor Medication Adherence

Poor Health

Outcomes

Increased Service

Utilization

Increased Health

Care Costs

Costs passed on to patient

8881

7823

4337 3908

4413 3756

1860 1258

0

2000

4000

6000

8000

10000

Annual Medical Spending Annual Total Spending

CHF HT DM CHOL

0

2000

Annual Rx Spending

Roebuch C. et al, Health Affairs, 2011, 30;1:91-99

Impact of Medication Adherence in Chronic Vascular Disease on Health Services use

(2005-2008)

The CV Polypill: A Cost Effective Strategy

Gaziano et al, Lancet 2006; 368:679-86

The CV Polypill: A Cost Effective Strategy

Ito et al, HSR 2012 47;6: 2097-2112

A Polypill Strategy for Secondary Cardiovascular Prevention

1. A new Global CVD Scenario: focus on accessibility to CV drugs

2. A polypill strategy to improve adherence to CV Medication

3. A Cost effective strategy for CV Prevention

4. From Concept to Reality

2002

Safety Bioequivalence

Formulation

RCT 1ary Prevention

Wald & Law ‘Vaccination Strategy’ 6 components > 55 Reduction > 80 %

Tolerability, BP, LDL-Chol TIPS-1 (2009) PILL (2011) TIPS-2 (2012)

Adherence

UMPIRE KANYINI-GAP IMPACT

EVOLUTION OF THE POLYPILL CONCEPT

2014 MACE HOPE-3 (2016)

TIPS-3 (2019)

Stroke PROPS

Castellano JM, Sanz G, Fuster V. Can J Cardiol. 2014 May;30(5):520-6.

2006

Post MI ASCVD DM

Outcomes & Cost

WHO-EML

PI: VALENTIN FUSTER Patients over 65 First ever AMI n=3200 7 countries RCT: Polypill vs. Usual care Primary outcome: MACE CV

death, recurrent MI, stroke, revascularization

Secondary outcomes: Adherence Risk factor control Cost-effectiveness

Trinomia Atorvastatin 40mgs.

Spain Austria

Germany Rumania Portugal

Italy México

Guatemala Nicaragua Honduras

El Salvador

DR

Argentina

Marketed : TRINOMIA/SINCRONIUM (ASR y AAR)

Approved: TRINOMIA (AAR), launch 2015

Sweden, Greece, Belgium, Bulgaria, Finland, France Poland, Ireland, Chez Republic

TRINOMIA (AAR), registration, launch 2015 - 2017

From Concept to Reality

Conclusions

1. The current global CV disease scenario demands cost effective strategies to improve adherence and accessibility to medications.

2. The perfect is enemy of the possible What can be done to assist the 50%+ patients not receiving recommended medications for secondary prevention?

3. Failure to address chronic disease global pandemic:

polypill as part of a comprehensive public health intervention

The undertreated are underrepresented in clinical

trials.

Medication Non-Adherence

“Increasing the effectiveness of adherence interventions may

have a far greater impact on the health of the population than any improvement in specific

medical treatments”

ADHERENCE TO LONG TERM THERAPIES: EVIDENCE FOR ACTION. WHO 2003